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| | <StructureSection load='7ake' size='340' side='right'caption='[[7ake]], [[Resolution|resolution]] 2.30Å' scene=''> | | <StructureSection load='7ake' size='340' side='right'caption='[[7ake]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7ake]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AKE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AKE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ake]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AKE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AKE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=RK8:4-[3-[(2~{S})-2-(6-bromanylpyridin-2-yl)oxypropyl]-2-methyl-imidazo[4,5-b]pyridin-5-yl]pyridine-2,6-diamine'>RK8</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=RK8:4-[3-[(2~{S})-2-(6-bromanylpyridin-2-yl)oxypropyl]-2-methyl-imidazo[4,5-b]pyridin-5-yl]pyridine-2,6-diamine'>RK8</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7aj2|7aj2]], [[7aj4|7aj4]], [[7aj5|7aj5]], [[7aj7|7aj7]], [[7aj8|7aj8]], [[7aja|7aja]], [[7ajm|7ajm]], [[7ajs|7ajs]], [[7ajv|7ajv]], [[7ajw|7ajw]], [[7ajy|7ajy]], [[7ak2|7ak2]], [[7aka|7aka]], [[7akb|7akb]]</div></td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DYRK1A, DYRK, MNB, MNBH ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </span></td></tr>
| + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ake FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ake OCA], [https://pdbe.org/7ake PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ake RCSB], [https://www.ebi.ac.uk/pdbsum/7ake PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ake ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ake FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ake OCA], [https://pdbe.org/7ake PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ake RCSB], [https://www.ebi.ac.uk/pdbsum/7ake PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ake ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN]] Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:[https://omim.org/entry/614104 614104]]. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.<ref>PMID:21294719</ref>
| + | [https://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN] Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:[https://omim.org/entry/614104 614104]. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.<ref>PMID:21294719</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN]] May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates.<ref>PMID:8769099</ref>
| + | [https://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN] May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates.<ref>PMID:8769099</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dual-specificity kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Dokurno, P]] | + | [[Category: Dokurno P]] |
| - | [[Category: Kotschy, A]] | + | [[Category: Kotschy A]] |
| - | [[Category: Surgenor, A E]] | + | [[Category: Surgenor AE]] |
| - | [[Category: Kinase selectivity]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Sbdd]]
| + | |
| - | [[Category: Serine/threonine-protein kinase]]
| + | |
| - | [[Category: Small molecule inhibitor]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
DYR1A_HUMAN Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:614104. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.[1]
Function
DYR1A_HUMAN May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates.[2]
Publication Abstract from PubMed
The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.
Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.,Weber C, Sipos M, Paczal A, Balint B, Kun V, Foloppe N, Dokurno P, Massey AJ, Walmsley DL, Hubbard RE, Murray J, Benwell K, Edmonds T, Demarles D, Bruno A, Burbridge M, Cruzalegui F, Kotschy A J Med Chem. 2021 May 12. doi: 10.1021/acs.jmedchem.1c00023. PMID:33975430[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ van Bon BW, Hoischen A, Hehir-Kwa J, de Brouwer AP, Ruivenkamp C, Gijsbers AC, Marcelis CL, de Leeuw N, Veltman JA, Brunner HG, de Vries BB. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin Genet. 2011 Mar;79(3):296-9. doi: 10.1111/j.1399-0004.2010.01544.x. PMID:21294719 doi:10.1111/j.1399-0004.2010.01544.x
- ↑ Shindoh N, Kudoh J, Maeda H, Yamaki A, Minoshima S, Shimizu Y, Shimizu N. Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21. Biochem Biophys Res Commun. 1996 Aug 5;225(1):92-9. PMID:8769099 doi:S0006-291X(96)91135-3
- ↑ Weber C, Sipos M, Paczal A, Balint B, Kun V, Foloppe N, Dokurno P, Massey AJ, Walmsley DL, Hubbard RE, Murray J, Benwell K, Edmonds T, Demarles D, Bruno A, Burbridge M, Cruzalegui F, Kotschy A. Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors. J Med Chem. 2021 May 12. doi: 10.1021/acs.jmedchem.1c00023. PMID:33975430 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c00023
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